Pulmonary hypertension (PH) is characterized by profound vascular remodeling and altered Ca²⁺ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Magnesium ion (Mg²⁺), a natural Ca²⁺ antagonist and a cofactor for numerous enzymes, is crucial for regulating diverse cellular functions, but its roles in PH remains unclear. Here, we examined the roles of Mg²⁺ and its transporters in PH development. Chronic hypoxia and monocrotaline induced significant PH in adult male rats. It was associated with a reduction of [Mg²⁺]_i in PASMCs, a significant increase in gene expressions of Cnnm2, Hip14, Hip14l, Magt1, Mmgt1, Mrs2, Nipa1, Nipa2, Slc41a1, Slc41a2 and Trpm7; upregulation of SLC41A1, SLC41A2, CNNM2, and TRPM7 proteins; and downregulation of SLC41A3 mRNA and protein. Mg²⁺ supplement attenuated pulmonary arterial pressure, right heart hypertrophy, and medial wall thickening of pulmonary arteries, and reversed the changes in the expression of Mg²⁺ transporters. Incubation of PASMCs with a high concentration of Mg²⁺ markedly inhibited PASMC proliferation and migration, and increased apoptosis, whereas a low level of Mg²⁺ produced the opposite effects. siRNA targeting Slc41a1/2, Cnnm2, and Trpm7 attenuated PASMC proliferation and migration, but promoted apoptosis; and Slc41a3 overexpression also caused similar effects. Moreover, siRNA targeting Slc41a1 or high [Mg²⁺] incubation inhibited hypoxia-induced upregulation and nuclear translocation of NFATc3 in PASMCs. The results, for the first time, provide the supportive evidence that Mg²⁺ transporters participate in the development of PH by modulating PASMC proliferation, migration, and apoptosis; and Mg²⁺ supplementation attenuates PH through regulation of Mg²⁺ transporters involving the NFATc3 signaling pathway.

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